Substituted pyrrolidinones and methods of preparation



United States Patent ()fiice 3,079,399 Patented Feb. 26, 191,53

3,079,399 SUBSTITUTED PYRROLlDlNONES AND METHODS OF PREPARATION Lawrence J. Exner, Cheltenham, Pa., assignor to Rohm & Haas Company, Philadelphia, Pa., a corporation of D la a No-Drawing. Filed May 12, 1960, Ser. No. 28,556

17 Claims. (Cl. 260.-.-325) This invention concerns Z-pyrrolidinones, which aresub; stituted in the -position by a 2 -oxo-4-cyano group, and the spirans corresponding to these substituted Z-pyrrolidinones that result from-the situation where the R substituentsdefined below, joining in-pairs .form carb ocyclic r-ingsaslprovided for hereinafter. These pyrrolidinones maybe represented by Formula I. Another embodiment of the invention provides for the-acids corresponding-to these 2-oxo-4.-cyanoalky1 substituted pyrrolidinones in which-the-cyano radical is replaced by acarboxyli-c group. A' further embodiment of: the invention provides for a process for preparing these 2-pyrrolidinones.-

The compounds of the invention may berepresented by the following formula V (I) in which the substituents R are defined further below.

'IheSFsubstituted -2-pyrrolidinones of the invention-may bedescribedas-dimerswhich-result from a method which comprises contacting a cyanoketonewhich; is further described below with astrong alkaline catalyst;

The cyanoketones which are employed as startingmaterials in the methodofthe. invention may be defined by the followingformula:

in which R R and'R are a hydrogen atom, an alkyl group containing 1 to 6 carbonatoms, or a hydrocarbon group containing from 5 to carbonatoms and includ: ing cycloalkyl, aralkyl, aryl, aud'alkaryl groups, the sub stituents which R R and R represent may be identical or not; also, R and R?, taken together with the carbon atoms to which they are bonded form a carbocyclic ringcontaining 5 to 6 carbon atoms, which in turn may have alkyl substituents containing each a totalof no more than four carbon atoms; R and R taken together with the carbon atom to which they are bonded, fornra carbocyclic ring containing 5 to 6carbon atoms, which in turn may have alkyl substituents containing each a total of no more than four carbon atoms; with the proviso that R R and'R are never all hydrogen atoms concurrently. Preferably, the total, number of. carbon atoms in these cyanoketones does not exceed twentyfour carbon atoms.

Illustrative of the cyanoketonesthat are useful reactants are the following:

3 methyl-4-oxopentanenitrile, 2,2-dimethyl-4-oxopentanenitrile, 2 methyl-Z-ethyl-4-oxopentanenitrile, Z-methyl 2-(2,2,4,4-tetramethylpentyl)-4-oxopentanenitrile, 2 methyl 2-neopentyl-4t-oxopentanenitrile, Z-acetyl-l-methylcyclopentanecarbonitrile, 2 acetylcyclohexanecarbonitrile, 2 methyl-Z-cyclohexyl-4eoxopentanenitrile, 1-( 2- oxopro-pyl)cyclopentanecarbonitrile, 1 (2-oxopropyl) cyclohexanecarbonitrile, 2 (l-pentyl-Z-oxopropyl)pentanenitrile, 2 acetyl-l-hexylcyclopentanecarbonitrile, 2- butyl- 2rnaphthyl-4aoxopentanenitrile, 3,3-dirnethyl- 2-(2- oxopropyl) bicyclo[2.2.1Jheptane-Z-carbonitrile, Z-heX- 2 3d 2f methyl-3 penty1 4 oxopentanenitrile, 2-benzyl 2 methyl 3jphenyl 4=oxopentanenitrileand the like. Most unexpectedly,levulonitrile fails to yield the correspondnsyc ic m r.-

The preparationofthe 5=substituted 2 pyrrolidinones of the inyenti-on comp-rises bringing together a cyanoketone of Formula II"with a strong alkaline catalyst: When two cyanoketones, that are dissimilar withrespect to at least one R substituent, are contacted with thealkaline catalystthere is formed, in addition to the dimersof the starting cyanoketonea addition products of the different cyanoketones. In the method of theinvention, the reaction isexothermic and, accordingly, the temperature isnot critical, except that for best yields, cooling may be app1ie d For the more sluggish cyanoketones some initial heating may be desirable to promote the start ofthevreactionunless i't is, desired to obtain this effect by adjustment of the type and/,or amount of basic catalyst.

Au overallitemperature range of .50"to 200 Cjmay besuggestedjfor the reaction, a lowerrangeas from 50 to 5 O Q beiug better suited for initiating the reactioncf thengore reactive cyanoketones, whereasvgenerally the preferredtemperaturerange extends from 0 to ,150."C. Since atmospheric pressures areentirely satisfactory, there is noneedfor sub} or superatmospheric pressures, As 31 Zreaction 1 proceeds and reaches towards completion, theheat abates untiljit is finally dissipated andthismay be ke a a conve ie tm u of he p ate eact on.

The eggactproportionof cyanoketone that" is, reacted is ,n:o t critical since the dimers-are readily formedunder the, conditions prescribed, regardless of the specific am un ed-ea h. ya o et ne s Generally, it,is .advantageous to carry out the reaction in an inert volatile organic solvent, such as aliphatic nd, aroma i ydrocarbons. the s, and st s,v u v as t y acetate. me y prop o a e, and? h like, en ne. oli ne, X len i cx ne, et y g i v li r s fl y e of ethyl nerglyco an he t e on us o the eacfionthe solv nt s eadi y e nov d'. hv s y r P ng, p ef a y. t e uc dp ssu es P efera ly nough o n s p es n v o, n ure pt mum te ac o tween the cyanoketone, andlfie basic catalyst.

In accordance with the invention, there isemployed a strong alkaline catalyst which promotes theformation of the addition products from the specified cyanoketones; For this purpose, there may be employed anywstrongbase. ypica are. t e alkal m t l d e l l a h met u h s: thi m, diu potassi m, ontium, ar m, and calcium; alkali metal oxides their hydrOXidessuchas o i m hydroxi e, pota sium hy ox d heirc x d s ascl t ium oxide, d um ox d a d po s u x de; the y d s uchasp j a m yan e 'a i i hium yanide; alkali metal lower alkoxides such as lithium butoxide, sodium methoxide, sodium t-butoxide and'potassiumrethoxide; alkali metal hydrides such as sodium hydride and potassium hydride; alkalijnetal amides such assodium amide, lithium amide, potassium amide; alkali metal lower alkyls, alkenyls and alkypyls such as methyl lithium, ethyl sodium, butyl potassium, allyl sodium, andbutenyl'potassium; phenylalkyl alkalimetals such. as benzyl sodiurn, phenylisopropylpotassium, sodium phenylacetylide and alkali metal aromatics such as phenyl sodium, phenyl lithium and phenyl potassium, phenyl buiyl' sodium; Alfin catalysts, which are commercial mixtures ofalkali metal alkenyls and'alkali metal alkenoxides, suchas allyl sodium with' sodium allyloxide and bntenylpotassiurn with od um ute oxi a d qua ern y mm mbases such as trimethylbenzylammonium hydroxide, and dimetlryldibenzylammoniu-m hydroxide and the corresponding alkoxides such as trimethylbenzylammoniumt buftoxide',

choline methoxide, and the like.

70%. yaluable pesticidal agents.

The proportion of the base which is used may range from the smallest catalytic amount which will promote reaction to an amount which causes its maximum practical speed with the individual cyanoketone selected. This proportion may vary from about 0.1 mole percent to about 30 mole percent of base, 0.5 to 10 mole percent generally giving an efficient rate of reaction, suitable adjustment of the amount of catalyst used being performed to best suit the individual cyanoketone and base selected.

As the reaction proceeds, solid product may separate from the solvent. When it is liquid, it is recovered by stripping, followed by recrystallization or distillation. Recrystallization of the product may be carried out in any suitable manner from the solvent used in the formation of addition product or from other suitable solvents, such as chlorinated hydrocarbons, such as ethylene dichloride, chloroform, and the like. The addition products are generally obtained in very good yields, usually in a yield over The products are useful compounds; they are In another valuable embodiment of the invention, there is provided the acids corresponding to the 2-pyrrolidinones of Formula I, which have, in the substituent bonded in the -position a carboxyl group in the 4-position instead of a nitrile group. These acids are prepared by a process which comprises hydrolyzing the pyrrolidinone of Formula I in the presence of a strongly basic medium to give a salt, and then by acidifying the medium, thereby freeing the acid from its salt. The heating temperature, in the presence of an aqueous base, is 50 to 150 C. and the preferred bases used are the hydroxides of alkali metals and alkaline earth metals. The pyrrolidinone and base are used in equimolar amounts but excess of base is preferred for optimum results. For the hydrolysis in presence of the base, any acid that effectively neutralizes the base may be used; strong mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, perchloric acid, tri- 'fiuoroacetic acid, trichloroacetic acid, phosphoric acid and the like are preferred.

The Z-pyrrolidinones of the invention are useful compounds in a variety of applications. They are also valuable starting materials for a number of chemical reactions. For instance, the nitrile substituted 2-pyrrolidinones of the invention readily yield the corresponding acids upon alkaline hydrolysis, no significant reversion to the starting acyclic acids occurring; other reactions include the formation of amides, especially the N-substituted amides, the formation of amidines and esters. The acids of the 2- pyrrolidinones of the invention can be reacted to give alkali metal and alkaline earth metal and quaternary ammonium salts.

Moreover, the 2-pyrrolidinones of the invention are useful pesticides, particularly in herbicidal, insecticidal, and fungicidal applications.

The present compounds may be used as stomach poisons for combatting agricultural pests such as bean beetle and armyworms. When compounded and dispersed into 25% wettable powders, and dispersed and applied at the rate of 2 lbs/100 gals. of water per acre, 3,3,5-trimethyl-5- (2 oxo 4 methyl-4-cyanopentyl)-2pyrrolidinone kills .over 70% of these insects. In fungicidal tests, complete kill of Stemphylium sarcinaeforme and of Monilinia fructicola is obtained in concentrations of 0.1% with 3,3,5-

trimethyl-S-(2-oxo-4-carboxypentyl)-2-pyrrolidinone. In

herbicidal applications, the present compounds are useful in controlling aquatic weeds in concentrations of 16 ppm.

In additional tests, indian mallow is controlled by preemergence applications.

In agricultural applications, the present compounds, either singly or in mixtures, are applied as dusts, wettable powders, self-dispersible concentrates, in solution or suspension. Compositions suitable as dusts are prepared 'from the 2-pyrrolidinones of the invention dispersed in a solid carrier, such as talc or clays. The compounds may be used in an amount ranging from A; to 25% or more,

if it is desired. As wettable powders, the compounds of the invention are mixed with a suitable wetting agent, such as a water-soluble surface-active polyethoxyalkylphenoxypolyethoxyethanol and a suitable dispersing agent, such as a formaldehyde condensed naphthalene sulfonate. The wettable powder may then be suspended in an aqueous medium and applied as a spray. Also, the 2-pyrrolidinones may be formulated into self-emulsifible or selfdispersible concentrates or as aqueous sprays.

The following examples, in which all parts are by weight unless otherwise indicated, are ofiered as further illustration of the compounds and method of the invention and are not intended to be construed as a limitation thereon.

EXAMPLE 1 In a reaction flask, there is placed 1 part of sodium methoxide in 72 parts of ethyl acetate and there are added 50 parts of 2,2-dimethyl-4-oxopentanenitrile in about 5 minutes as temperature rose to 45 C. During the short exotherm, the temperature was maintained at the range of 40 to 45 C. Solid soon precipitated. After standing for about 3 hours, there are added 135 parts more of ethyl acetate and the mixture is heated to reflux to ensure solution. After adding 2.4 parts of concentrated hydrochloric acid, sodium chloride precipitates. It is filtered off. Cooling the filtrate a yield of 37.2 parts of 3,3,S-trimethyl-S-(2-oxo-4-cyanopentyl)-2- pyrrolidinone with a MP. of 136 to l37.5 C. is obtained. Two parts of crude (130-135 C.) solid was obtained. The product contains 67.3% carbon (67.2% theoretical), 8.8% hydrogen (8.9% theoretical), 11.3% nitrogen (11.2% theoretical) and has a molecular weight of 250.

Instead of using sodium methoxide, there is employed an equivalent amount of potassium ethoxide with similar results. Similarly, potassium ethoxide is substituted by sodium amide and lithium oxide; the same product is obtained.

EXAMPLE 2 Hydrolysis of 3,3,5-Trimethyl-5-(20xo-4-Cyanopentyl)- Z-Pyrrolidinone Five parts of this dimer is refluxed with 6.8 parts barium hydroxide in parts of water for 7 hours until evolution of ammonia ceased. The barium is precipitated with 0.5 normal sulfuric acid. Upon evaporation to parts of water and cooling to 0 C., 2.6 parts of solid having a MP. of to 143 C. precipitated and recrystallized from water. The neutralization equivalent is 281 and the nitrogen content is 5.01. Calculated values for the dimer acid are neutralization equivalent269 and nitrogen content 5.2.

Instead of using barium hydroxide, the dimer is refluxed with an equivalent amount of sodium hydroxide and hydrochloric acid is used for neutralization. The acid corresponding to the dimer is obtained in good yields.

EXAMPLE 3 There are mixed 11.1 parts of 3-methyl-4-oxopcntanenitrile and 0.25 part of sodium methoxide. The exothermic reaction lasting about ten minutes takes place; it is controlled to 4550 C. After standing a few hours, the mixture sets to a solid which is recrystallized from ethyl acetate. The product, 4,5-dimethyl-5-(2-oxo-3- methyl-4-cyanobutyl)-2-pyrrolidinone, melts at 117- 119 C. and has a molecular weight of 230:4; calculated for the dimer-222.

Likewise, 2-methyl-2-ethyl-4-oxopentanonitrile, in the presence of sodium hydride, yields 3,5-dirnethyl-3-ethyl- 5 2-oxo-4-methyl-4-cyclohexyl) -2-pyrrolidinone.

EXAMPLE 4 4.4 parts of 4,5-dimethyl-5-(2-oxor3-methyl-4-cyanobutyl)-2-pyrrolidinone, is refluxed with 3.7 parts of barium hydroxide in 45 parts of water for about ten hours. The barium is precipitated with dilute H 80 Evaporation of most of the water and cooling gives a good yield of 4,5-dimethyl-5-(2-oxo-3-methyl-4-canboxybutyl) 2-pyrrolidinone.

Substitution of sulfuric acid by methanolic hydrogen chloride yields the same pyrrolidinone product.

EXAMPLE Ilikewise, 2-butyl-2-naphthyl-4-oxopentanenitrile produces 3-naphthyl-3-butyl-5-methyl-5-(2-ox0-4-naphthyI-4- cyanooctyl)-2-pyrrolidinone,

Substitution of potassium butoxide by-equal weights of butyl, lithium, sodium acetylide, dimethyl magnesium yields 3-phenvl 5 methyl-5-(2-oxo-4-phenyl-4-cyanobu tyl).-2-pyrrolidi none in good yields.

XAMPLE. 6

Hydrolysis of 3-Phenyl-5.-Methyl-5 (2r0x0-4 Phenyl4 Cyanobutyl) -2-Pyrrolidin0ne 6.9 parts of this dimer. isrefiuxed with 3.7 parts of barium hydroxide in 40 parts of water for about twenty hours. The product, 3-phenyl-5-methyl-5-(2-oxo-4-phenyl-4-carboxybutyl)-2-pyrrolidinone, is isolated as described in Example 4.

Trimethylbenzyl ammonium hydroxide is substituted for barium hydroxide with equivalent results.

EXAMPLE 7 There are mixed 18.1 parts of 2-methyl-2-neopentyl-4- oxopentanonitrile and 2.4 parts of a 75% methanol solution of benzyltrimethylamminoum methoxide. As the exothermic reaction ceases, the mixture is heated one hour on a steam bath. Recrystallization of the crude product gives the product, 3,5-dimethyl-3-neopentyl-5-(2- oxo-4-neopentyl-4-cyanopentyl) -2-pyrrolidinone.

EXAMPLE 8 Hydrolysis of 3,5-Dimethyl-3-Ne0pentyl-5-(2-Ox0-4-Neopentyl4-Cyan0pentyl)-2-Pyrrolidinone There are refluxed 7.2 parts of this dimer with 3.7 parts of barium hydroxide in water for thirty hours. The product, 3.S-dimethyl-3-neopentyl-5-(2-oxo-4-neopentyl-4- carboxypentyl)-2-pyrrolidinone, is isolated as described in Example 4.

EXAMPLE 9 There are mixed 15.1 parts of 2-acetylcyclohexanecarbonitrile and 1.24 part of sodium phenylacetylide. One half hour after mixing, the reactants are heated on a steam bath to 50 C. for one hour. After two days of storage at 5 0, crystals of the 3-methyl-3-(Z-cyanocyclohexanecarbonylmethyl) 1,3,3a,4,5,6,7,7a octahydro 1 isoindolone are obtained.

2-methyl-2-cyclohexyl-4-oxopentanenitrile yields 3,5-dimethyl 3 cyclohexyl 5 (2 oxo 4 cyclohexyl 4- cyanopentyl)-2-pyrrolidinone when treated in the manner 6 shown above. Likewise, 2'-acetyl-l-methylcyclopentanecarbonitrile in presence of lithium butoxide yields- Cyclopentyl s- .3. lo ptrli- 0= CHi-C-Q -'-C'- H:

on. 0 N

3,3 dimethyl 2 -(2 oxopropyl)bi cyc lo(2.2 .1)heptanone-Z-carbonitrile, when allowed to heat in the presence of potassium t-butoxide to about 35 C., gives ydro s s f; -Metl -r -3-(ZrQva y xqneca bqny methyl)7 .3544.illw rahydrqr q aiqlon There are refluxed-6 parts-of this .dimer with 3 .7' parts of barium hydroxide -inwater for 30 hours. The prod uct, 3-methyl- 3-(2-carboxycyclohexanecarbonylmethyl)- 1,3,3a,4,5,6;7;7a-octahydro-1 isoindolone; is isolated as described in Example 4; Substitution of-sulfuric acid-by (a) R R and R when taken individually, are selected from the group consisting of a hydrogen atom and a group selected from the class consisting of an alkyl of l to 6 carbon atoms and a hydrocarbon group of 5 to 10 carbon atoms selected from the class consisting of cyc'loalkyl, aralkyl, aryl, and alkaryl;

(b) R and R when taken together with the carbon atoms to which they are bonded form a saturated car-- bocyclic ring of 5 to 10 carbon atoms; and

(c) R and R when taken together with the carbon atom to which they are bonded, form a saturated carbocyclic ring of 5 to 10 carbon atoms;

with the proviso that R R and R are never all hydrogen atoms concurrently.

2. A cyanoketone of the Formula I of claim 1, in which R is an alkyl group of from 1 to 6 carbon atoms,

R is a hydrogen atom, and

R is an alkyl group of from 1 to 6 carbon atoms.

3. A cyanoketone of the Formula I of claim 1, in which R is a hydrogen atom, and

R and R taken together with the carbon atom to which they are bonded, form a saturated carbocyclic ring of 5 to 10 carbon atoms.

4. A cyanoketone of the Formula I of claim 1 in which R and R taken together with the carbon atoms to which they are bonded, form a saturated carbocyc'lic ring of 5 to 10 carbon atoms, and

R is a hydrogen atom.

5. A cyanoketone of the Formula I of claim 1 in which R is a hydrocarbon aryl group of from 6 to 10 carbon atoms, and

R and R are alkyl groups of 1 to 6 carbon atoms.

6. 3 methyl 3 (2 cynanocyclohexanecarbonylmethyl)-1,3,3a-4,5,6,7,7a-octahydro-l-isoindolone.

7. 3,3,5 trimethyl 5 (2 oxo 4 cyanopentyl) 2- pyrrolidinone.

in which (a) R R and R when taken individually, are selected from the group consisting of a hydrogen atom and a group selected from the class consisting of an alkyl of 1 to 6 carbon atoms and a hydrocarbon group of to 10 carbon atoms selected from the class consisting of cycloalkyl, aralkyl, aryl, and alkaryl; V -(b) R and R when taken together with the carbon atoms to which they are bonded, form a saturated carbocyclic ring of 5 to 10 carbon atoms; and (c) R and R when taken together with the carbon atom to which they are bonded, form a saturated car-bocyclic ring of 5 to 10 carbon atoms; with the proviso that R R and R are never all hydrogen atoms concurrently.

12. A process for preparing adducts of the formula R: l H Rs c ru B R a o: oHr( 3oH- --B N CH3 0 N in which (a) R R and R when taken individually, are selected from-the group consisting of a hydrogen atom and a group selected from the class consisting of an alkyl of l to 6 carbon atoms and a hydrocarbon group of 5 to 10 carbon atoms selected from the class consisting of cycloalkyl, aralkyl, aryl, and alkaryl;

(b) R and R when taken together with the carbon atoms to which they are bonded form a saturated carbocyclic ring of 5 to 10 carbon atoms; and

(c) R and R when taken together with the carbon atom to which they are bonded, form a saturated carbocyclie ring of 5 to 10 carbon atoms; with the proviso that R R and R are never all hydrogen atoms concurrently; which comprises reacting with a strong alkaline catalyst 21 cyanoke-tone of the formula in which R R and R are defined above at a temperature in the range of about to 200 C.

13. The process of claim 12 in which the reaction is carried out at a reaction temperature in the range of about 0 to C.

14. The process of claim 12 in which the reaction is carried out in the presence of an inert organic solvent.

15. A process for the preparation of 3,3,5-trirnethyl-5- (2-oxo-4-cyanopentyl)-2-pyrrolidinone which comprises reacting 2,2-dimethyl-4-oxopentane nitrile with sodium methoxide.

16. A process for preparing 4,5-dimethyl-S-(2-oxo-3- methyl-4cyanobutyl)-2-pyrrolidinone which comprises reacting 3-methyl-4-oxopentanenitrile with sodium methoxide.

17. A process for preparing 3-phenyl-5-rnethyl-5-(2- oXo-4-phenyl-4-cyanobutyl)-2-pyrrolidinone which comprises reacting 2-pheny1-4-oxopentanenitrile with potassium butoxide.

No references cited 

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
 6. 3- METHYL -3- (2-CYANOCYCLOHEXANECARBONYLMETHYL)-1,3,3A,4,5,6,7,7A-OCTAHYDRO-1 -ISOINDOLONE. 